Abstract Body: Background:
Atherosclerosis remains a leading cause of morbidity and mortality. Recent evidence suggests that plaque formation is mediated by dysregulated yes-associated protein 1 (YAP) signaling in vascular and immune cells within the arterial wall. To address this pathology, we previously established that targeted delivery of the YAP inhibitor verteporfin (VP)—via monocyte membrane-coated nanoparticles (MoNP)—effectively reduces endothelial inflammation and attenuates plaque formation in mice. Building on those findings, this study utilizes single-cell profiling to dissect the pharmacodynamics of MoNP-VP and evaluates their therapeutic efficacy in treating established plaques, highlighting the translational potential of this biomimetic nanotherapy.

Hypothesis:
Beyond targeting YAP in inflamed endothelial cells, MoNP-VP modulates smooth muscle cell dysfunction and immune cell infiltration to restrict plaque progression.

Methods:
Wildtype mice were given a single intravenous injection of adeno-associated virus carrying a gain-of-function mutant of proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9) and maintained on a high-fat diet (HFD) for 16 weeks to establish plaques. They were then randomized to continue HFD (persistent hypercholesterolemia) or switch to a chow diet (simulated lipid-lowering therapy) while receiving biweekly MoNP-VP or vehicle MoNP for 6 weeks. Post-sacrifice analyses included quantification of plaque burden, inflammatory cell content, and histological composition.

Results:
Single-cell profiling revealed that MoNP-VP treatment remodeled the cellular landscape of the arterial wall, significantly depleting the foamy macrophage population while expanding the smooth muscle cell/fibroblast cluster. In the persistent hypercholesterolemia model, MoNP-VP reduced macrophage infiltration and attenuated plaque progression relative to controls. While the diet switch alone reduced the overall plaque burden, the addition of MoNP-VP further suppressed macrophage accumulation. Importantly, MoNP-VP increased fibroblast content and collagen deposition across both dietary conditions. These results demonstrate that MoNP-VP attenuates vascular inflammation and promotes plaque stabilization.

Conclusion:
MoNP-VP treatment not only effectively blocks early plaque formation but also promotes a more stable phenotype in existing plaques, offering a promising nanomedicine strategy for managing lesion progression alongside lipid-lowering therapies.